1G). the treatment of bone metastatic cancers and other bone diseases. == INTRODUCTION == Antibody-based therapies, including those using monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, checkpoint inhibitors, as well as others, have realized their clinical potential in terms of their power to treat a variety of cancers (14). Nevertheless, despite the fact that most therapeutic antibodies have high affinities for their targets, the presence of these same targets in normal tissues can markedly limit the ability of therapeutic agents to hit their targets without inducing unacceptable on-target toxicity in healthy cells (57). Furthermore, low levels of delivery of therapeutic antibodies to some tissues such as brain or bone can significantly limit their efficacy in treating diseases in these tissues (8). Thus, it is likely that enhancing both the antigen MAP2K2 and tissue specificity of antibodies will ultimately transform CRAC intermediate 2 the efficacy of antibody therapy for clinical treatment of cancer. Half of patients with an initial diagnosis of metastatic breast cancer (BCa) will develop bone metastases (9). Patients having only skeletal metastases usually have a better prognosis than patients with vital organ metastases (9,10). Furthermore, bone metastasis is associated with severe symptoms such as spinal cord compression, pathological fractures, and hypercalcemia (11). Despite our deep understanding of molecular mechanisms (12,13), effective therapies that can eliminate malignancy cells in the bone niche are still lacking (14). The bone is also not the final destination of metastatic dissemination. Recent genomic analyses have revealed frequent metastasis-to-metastasis CRAC intermediate 2 seeding (1517). More than two-thirds of bone-only metastases subsequently develop secondary metastases to other organs, ultimately leading to the death of patients (9,10). Some metastases initially identified in non-bone organs are actually the result of seeding from subclinical bone micrometastases (BMMs). This apparently is the result of cancer cells initially arriving in the bone and then acquiring more aggressive phenotypes that allow them to establish more overt metastases in both bone and other sites (18). It should therefore be useful to develop strategies for preventing BMMs from establishing more overt metastases in both bone and non-bone tissues. While targeted antibody therapy and immunotherapy are now emerging as new avenues for treating metastatic BCa, the performance of these agents in patients with bone metastases has been disappointing. For example, trastuzumab (Tras; Herceptin) and pertuzumab (Perjeta) antibodies targeting human epidermal growth factor receptor 2 (HER2) have been used to treat patients in adjuvant and metastatic settings. Although many BCa patients benefit from these treatments, in large numbers of BCa patients with bone metastasis, the disease progresses within 1 year, and few patients experience prolonged remission (1922). In another phase 3 clinical trial testing atezolizumab in patients with metastatic triple-negative BCa, progression-free survival was significantly longer in the atezolizumab group than in the placebo group. However, among BCa patients with bone metastases, no significant difference was observed between the atezolizumab-treated and placebo groups for risk of progression or death (23). Therapies with improved outcomes for BCa patients with bone metastases are therefore highly desired. Attempts to ensure effective concentrations of a therapeutic drug in the bone unavoidably lead to high concentrations in other tissues as well, often resulting in adverse systemic effects or side effects that may limit or exclude the use of the drug (24,25). In this case, the potential benefit of passive targeting is usually lost. Here, we describe an innovative bone-targeting (BonTarg) technology that enables the tissue-specific delivery of therapeutic antibodies to the bone via conjugation CRAC intermediate 2 of bone-targeting moieties. The resulting bone-targeting antibodies can specifically target the bone metastatic niche to eliminate BMMs and also prevent seeding of multiorgan metastases from bone lesions. Taking advantage of the high mineral concentration unique to the bone hydroxyapatite (HA) matrix, bisphosphonate (BP) conjugation has been used for selective delivery of small molecule drugs, imaging probes, nuclear medicines, and nanoparticles to the bone as a means of treating osteoporosis, primary and metastatic bone neoplasms, and other bone disorders (24,2630). Negatively charged BP has a high affinity for HA, which is the main component of hard bone, resulting in preferential binding to the bone. However,.